Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations

Am J Med Genet A. 2006 Mar 1;140(5):463-70. doi: 10.1002/ajmg.a.31101.


Hereditary hemorrhagic telangiectasia (HHT) is a genetically heterogeneous vascular dysplasia with multiple telangiectases and arteriovenous malformations and it is caused by mutations in endoglin gene (ENG) (HHT1) and activin A receptor type II-like 1 gene (ACVRL1) (HHT2). We evaluated 111 patients with HHT from 34 families by history, examination, screening for vascular malformations, and sequencing of both genes. We found mutations in 26 of the 34 kindreds (76%) analyzed-54% were in ENG and 46% were in ACVRL1. Mutations in ACVRL1 cluster largely in exons 7 and 8, but ENG mutations were widely distributed within that gene. We found that epistaxis had an earlier onset in patients with HHT1 than those with HHT2, but the severity by middle ages was similar. Pulmonary arteriovenous malformations were more frequent and on the average of larger size in HHT1. Hepatic vascular malformations were more common in patients with HHT2. Cerebral arteriovenous malformations were more common in patients with HHT1, but spinal arteriovenous malformations were seen only in patients with HHT2. Truncating mutations in ENG were associated with more affected organs and more severe hemorrhaging than were missense mutations. We conclude that HHT2 has a later onset than HHT1 and the former may disproportionately involve smaller vessels in tissues with more significant vascular remodeling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type II / genetics
  • Anemia / etiology
  • Antigens, CD / genetics
  • Central Nervous System Diseases / etiology
  • DNA Mutational Analysis
  • Endoglin
  • Epistaxis / etiology
  • Face / blood supply
  • Face / pathology
  • Female
  • Gastrointestinal Hemorrhage / etiology
  • Genotype
  • Humans
  • Liver Diseases / etiology
  • Lung Diseases / etiology
  • Male
  • Mouth / blood supply
  • Mouth / pathology
  • Mutation*
  • Phenotype
  • Receptors, Cell Surface / genetics
  • Telangiectasia, Hereditary Hemorrhagic / classification
  • Telangiectasia, Hereditary Hemorrhagic / complications
  • Telangiectasia, Hereditary Hemorrhagic / genetics*
  • Telangiectasis / etiology


  • Antigens, CD
  • ENG protein, human
  • Endoglin
  • Receptors, Cell Surface
  • ACVRL1 protein, human
  • Activin Receptors, Type II